Ion-sensitive electrodes are known to the prior art for use in measuring the activity of a specific ion, or ions, in a test solution. In the case where the test solution comprises bodily fluids, the ion activities typically measured are those of the hydrogen, sodium, potassium, and calcium cations (respectively H.sup.+, Na.sup.30 , K.sup.+, and Ca.sup.2+). Typically, the ion-sensitive electrode are a reference electrode are immersed in the test solution. The ion-sensitive electrode may, in one instance, be constructed with an ion-exchanging membrane so that the potential difference between the ion-exchanging membrane and the test solution is a function of the activity of a particular ion in the test solution. The reference electrode is constructed so that the potential difference between the reference electrode and the test solution is a constant independent of the composition of the test solution. By measuring the voltage across the ion-sensitive electrode and the reference electrode, the activity, and therefore the concentration, of a particular ion in the test solution may be determined.
The construction of a typical ion-sensitive electrode known to the prior art for measuring the activity of hydrogen ions (otherwise referred to as a pH electrode) is seen in FIG. 1. A metallic conductor 10, typically a silver wire coated with silver chloride, is immersed in an inner reference solution 12, typically composed of a weak hydrogen chloride or other solution having a known and constant pH, which is contained within a sealed glass tube 14. One end of the tube 14 is closed by a thin membrane 16 which is handblown from a pH-sensitive glass. It is known in the prior art that when certain glasses, for example, that marketed by Corning Glassworks as Code 0150 glass, having a norminal mole-percent composition of 22%, Na.sub.2 O, 6% CaO, and 72% SiO.sub.2, are constructed in very thin membranes (less than 100 microns) and immersed in a test solution, a very thin hydrated layer (typically 100 A) is formed on the membrane surface in contact with the test solution which apparently permits the exchanger of sodium ions in the glass for hydrogen ions in the test solution. The result of this ion exchange is the development of a potential difference between the membrane and the test solution which is related to the hydrogen ion activity in the test solution.
The overall potential difference between the metallic conductor 10 and the test solution may be visualized as the sum of the potential differences between the metallic conductor 10 and the inner reference solution 12; across the inner reference solution 12; between the inner reference solution 12 and the membrane 16; across the membrane 16; and, between the membrane 16 and the test solution. It has been shown that all of these potential differences, with the exception of the potential difference between the membrane 16 and the test solution, are substantially constant with respect to the pH of the test solution.
Since the potential difference between the reference electrode and the test solution is substantially constant and independent of pH, the potential difference between the pH electrode and the reference electrode, when immersed in the test solution, varies linearly with pH at a given temperature according to the well-known equation ##EQU1## where V.sub.o is an electrode-dependent contant, k is Boltzmann's constant, T is the temperature of the test solution in degrees Kelvin, e is the charge on an electron, and pH is the hydrogen ion concentration of the test solution in pH units. At room temperature of 300.degree. Kelvin, the potential difference changes linearly by approximately 59mv/pH unit.
While pH electrodes of the aforementioned construction provide acceptable pH response in industrial or medical applications in which the pH electrode is immersed in a test solution contained within a receptacle, they have proved unsuitable for in vivo medical applications in which the pH electode and the reference electrode are brought into contact with bodily fluids contained within a body receptacle or cell. Experimenters in the prior art have sought to construct ion-sensitive electrodes, including pH electrodes, for in vivo applications by reducing the dimensions of the ion-sensitive electrodes to dimensions compatible with body receptable and cellular structure. Such electrodes, oftentimes termed "microelectrodes" are difficult to make, inasmuch as a highly trained glass blower must blow the glass membrane of the electrode by hand. Because of their small size, such microelectrodes are very fragile and thus structurally unsuitable for most in vivo applications. The fragility of the microelectrodes also requires that a large quantity of such microelectrodes be fabricated in order to achieve a required number of acceptable microelectrodes due to microelectrode breakage. Since each microelectrode is handmade, uniformity cannot be guaranteed among microelectrodes so that detailed calibration tests must be run. Because of the aforementioned difficulty of manufacture, fragility, and testing procedures, individual microelectrodes are quite expensive and are therefore uneconomic for in vivo applications in which a large number of such microelectrodes may be used and then disposed of.
In attempts to construct acceptable microelectrodes for in vivo medical applications, experimenters have developed various types of solid-state devices fabricated by means of certain thin-film integrated circuit techniques. Among these solid-state devices are those identified as CHEMFETs or ISFETs, standing, respectively, for chemically-sensitive and ion-sensitive field effect transistors. In these devices, the conductor normally applied to a gate insulating region of the field effect transistor is not utilized, and the gate insulating region is itself fabricated out of an ion-sensitive material. Because the ion-sensitive material must be bonded to the substrate of the field effect transistor, typically high purity silicon, and must be limited in its thickness to typically less than a micron, the only ion-sensitive materials conveniently fabricated in the prior art by thin-film techniques on a silicon substrate are silicon dioxide (SiO.sub.2) or silicon nitride (Si.sub.3 N.sub.4), or a combination of these materials. Accordingly, the best-characterized and desirable membrane materials, including ion-sensitive glasses such as Corning Code 0150 glass, cannot be used.
The experimenters of the prior art have also attemped to dispense with the inner reference solution by providing an ion-sensitive electrode in which a metallic conductor is in direct contact with an ion-sensitive, glass membrane. These electrodes, often referred to as "metal-connected" glass electrodes, typically are constructed by plating or otherwise applying a metallic conducting layer directly on a performed member including a thin membrane of the desired ion-sensitive glass. As yet another example of such metal-connected glass electrodes, an element comprising a conductor has a surface layer of an electrochemically active metal. This surface layer is coated with a first coating of a mixture of glass and a halide of the active metal. Preferably, the active metal is copper and the halide is copper chloride. An ion-sensitive glass membrane, or second coating, is then formed over the first coating by dipping the conductor into a molten bath of ion-sensitive glass so as to cover entirely the first coating. The conductor is then removed from the molten bath and the glass is allowed to cool and to solidify into the desired membrane.
While such metal-connected glass electrodes of course dispense with the need for an inner reference solution and are more rugged in their construction than ion-sensitive electrodes including such an inner reference solution, they have not been capable of providing repeatable and determinable responses to specific ion activities.
There are quite a number of other ion-sensitive electrodes, and processes for making the same, that have been proposed in the prior art and that are subject to one or more of the shortcomings of the prior art ion-sensitive electrodes discussed in detail herein.
It is therefore an object of this invention to provide an improved ion-sensitive electrode.
It is a further object of this invention to provide such an improved ion-sensitive electrode which can be fabricated as a microelectrode suitable for in vivo medical applications.
It is yet a further object of this invention to provide such an improved ion-sensitive electrode fabricated as a microelectrode which is rugged in construction, and which can be inexpensively mass-produced.
It is another object of this invention to provide microelectrodes which, when mass-produced, exhibit repeatable and determinable responses to specific ion activities.
It is still another object of this invention to provide an improved ion-sensitive electrode which is electrically stable, low in noise and electronically compatible with standard silicon-based integrated circuits.
Yet another object of this invention is to provide an ion-sensitive electrode which can be fabricated by thin-film and thick-film integrated circuit processes, and various combinations thereof.
Still another object of this invention is to provide thin-film and thick-film integrated circuit processes for fabricating ion-sensitive electrodes.
A further object of this invention is to provide thin-film and thick-film integrated circuit processes for ion-sensitive electrodes which permit the best-characterized and desirable membrane materials, including ion-sensitive glasses, to be used.
Still a further object of this invention is to provide thin-film and thick-film integrated circuit processes which permit ion-sensitive electrodes to be inexpensively and uniformly mass-produced.
It is also an object of this invention to provide an improved ion-sensitive electrode, and processes of making the same, which eliminates in most cases the need for the inner reference materials used in prior art ion-sensitive electrodes.
A particular object of this invention is to provide an improved pH electrode, suitable for in vivo medical applications, and processes for making such an improved pH electrode.